Citations

Abstract Introduction Skull base neuroanatomy is traditionally learned through two-dimensional anatomical atlases, which while are of unquestionable value, lack the nuanced association of three-dimensional relationships between fundamental anatomical structures relevant to surgical approaches. Surgically focused step-by-step anatomical dissections can augment trainee learning of complex skull base techniques, particularly multistep and nuanced techniques such as translabyrinthine and transcochlear approaches. Methods Translabyrinthine and transcochlear approaches were performed on six sides of three formalin-fixed latex-injected specimens. The study objective was the completion and photo documentation of the steps involved in the approach in order to provide a comprehensive, intelligible, and anatomically oriented resource for multilevel trainees. Illustrative case examples were prepared to supplement approach dissections. Results The translabyrinthine and transcochlear approaches offer unique lateral windows through the temporal bone into the posterior fossa, providing excellent access to pathology at the petrous apex, internal auditory canal, Meckel's cave, and anterolateral brainstem. The transcochlear approach, which is an anterior extension of the translabyrinthine, particularly provides excellent exposure of the prepontine region and clivus. Important surgical considerations include patient position, temporal bone drilling and identification of critical landmarks, dural opening and identification of neurovascular structures, and reconstruction/closure techniques. Conclusion The translabyrinthine and transcochlear approaches are fundamental techniques for lateral skull base and posterior fossa pathologies. Both approaches are hearing-sacrificing but often require minimal to no cerebellar retraction and deliver unique visualization of prepontine neurovascular structures. This step-by-step approach guide provides a unique practical and high-yield surgically oriented learning resource for neurosurgery and otolaryngology trainees.

Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Abstract Confounding results of engineered mesenchymal stem cells (MSCs) used as cellular vehicles has plagued technologies whereby success or failure of novel approaches may be dismissed or inaccurately ascribed solely to the biotechnology platform rather than suitability of the human donor. Polymeric materials were screened for non‐viral engineering of MSCs from multiple human donors to deliver bone morphogenic protein‐4 (BMP4), a protein previously investigated in clinical trials for glioblastoma (GBM) to combat a subpopulation of highly invasive and tumorigenic clones. A “smart technology” that target the migratory and stem‐like nature of GBM will require: (1) a cellular vehicle (MSC) which can scavenge and target residual cells left behind after surgical debulking and deliver; (2) anti‐glioma cargo (BMP4). Multiple MSC donors are safely engineered, though varied in susceptibility to accept BMP4 due to intrinsic characteristics revealed by their molecular signatures. Efficiency is compared via secretion, downstream signaling, differentiation, and anti‐proliferative properties across all donors. In a clinically relevant resection and recurrence model of patient‐derived human GBM, we demonstrate that nanoengineered MSCs are not “donor agnostic” and efficacy is influenced by the inherent suitability of the MSC to the cargo. Therefore, donor profiles hold greater influence in determining downstream outcomes than the technical capabilities of the engineering technology.

This study investigates delays in transitioning from positive noninvasive multitarget stool DNA test results to scheduled diagnostic colonoscopies and identifies strategies aimed at improving patient care. A retrospective review revealed a 53% reduction in the average time from positive multitarget stool DNA test results to ordering colonoscopies postintervention. The findings demonstrate the significance of implementing a new communication system to expedite transitions in health care processes, showcasing its potential to significantly improve efficiency in patient care and health care provider workflows across various clinical testing scenarios. The findings emphasize the transformative impact of this communication system, shedding light on its ability to streamline processes and enhance patient care and staff experience.

Abstract Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro‐inflammatory senescence‐associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age‐related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age‐associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C 12 FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C 12 FDG + PBMCs that is commensurate with increases in age and senescence‐related serum biomarkers. Interestingly, C 12 FDG + PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C 12 FDG + PBMCs and age‐related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age‐related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C 12 FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.